PROJECT SUMMARY OVERALL This application seeks continued support for the Washington University DDRCC (WU-DDRCC). The overall objective of the WU-DDRCC is to create an infrastructure that supports collaborative, multidisciplinary investigation into host-environment interactions in digestive disease. The WU-DDRCC provides enabling technology that promotes the basic and translational research interests of its 50 Full + 22 Associate members, and nurtures career development of junior investigators. Our Research Base is highly productive as evidenced by 248 original peer reviewed publications citing the DDRCC (60% reflecting collaborations involving two or more members), including 58 in journals with impact factors >10, and increased funding support ($23.8M?$30.9M; 30% increase since 2013). Our members have appointments in 13 different Departments across Washington University. The Research Base interests are organized around three mechanistic themes: (1) Host-microbial interactions, inflammation and mucosal immunity; (2) Stem cells, epithelial renewal, paligenosis and cancer; (3) Metabolic homeostasis, nutrient transport and enterohepatic signaling. The Research Base is supported by three Biomedical Cores that leverage institutional resources, and which have evolved in response to members' needs to provide a cost-effective infrastructure. These Cores include (1) Advanced Imaging and Tissue Analysis Core (AITAC), which provides sophisticated imaging technologies; (2) A new Precision Animal Models and Organoids Core (PAMOC), which provides mouse genetic services and organoid technologies; and (3) a Biobank Core, which provides access to clinical biospecimens from normal and disease states. These Cores are overseen by a responsive Administrative Core (ARAC), guided by both Internal and External Advisory Boards to promote collaborative and synergistic interactions and support Biomedical Cores and services that reflect current and future needs of the Research Base with state-of-the-art services and specialized expertise, delivered cost- effectively and efficiently. The WU-DDRCC also supports a scientific Enrichment Program sponsoring visiting researchers and workshops to augment the scientific milieu, promote collaboration and stimulate development of new initiatives in digestive disease. The Enrichment Program also promotes academic career development by nurturing the interests of postdoctoral trainees, fellows and junior faculty, including promoting diversity in the workforce through a targeted Underrepresented Minority speaker program. The WU-DDRCC has invested significant resources and effort in building a pipeline of future leaders in digestive disease research by supporting and nurturing new investigators through an annual Pilot and Feasibility Program for which there is greater than 39:1 return on investment over the last 15 Years (3 cycles) of this award. In addition, the WU-DDRCC is committed to promoting and sharing technology development with NIDDK funded Centers locally as well as other DDRCCs regionally, through the Midwest Alliance and the NIDDK Center program. Collectively, these accomplishments serve to advance discovery in digestive disease that will impact patient care.